(Adapted from the application): This project will undertake the development of novel methods to analyze the structures of macromolecules that their complexes using energy based models, focusing primarily on electrostatic interactions. One of the fundamental difficulties in understanding the energetics of binding is that most of the interactions are exchange reactions; that is, chemical groups trade interactions with solvent in the unbound state for interactions with the binding partner in the bound state. A novel innovation introduced here is the definition of an electrostatic complement, the optimal tradeoff between unfavorable desolvation energy and favorable interactions in the complex. This essentially inverts the design problem, designing the properties of the optimal based on physical principles, and provides a clear and precise standard that can be compared to trial ligands and that can be used as a template in the modification of existing ligands and the de novo construction of new ligands. The PI has developed methods to solve, for this complement, using simplified geometrics. The aim is to extend those methods to arbitrarily shaped molecules, to develop methods for using the optimal electrostatic complement in ligand discovery, and to extend current methods for the analysis of conformationally flexible ligands. The methods will be tested and validated initially using the well- characterized class II MHC molecule and the HIV protease. Further design efforts will proceed with other targets characterized within this program.